Excellence in Research: Role of the T3SS effector EseN of E. ictaluri in virulence and host immune response.

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Catfish are a food source around the world. Reducing fish loss is an essential task in the catfish industry for food security. Edwardsiella ictaluri is a bacterium, and it is a leading cause of catfish disease and loss. The goal of this project is to identify how this bacterium causes disease and death in catfish. We show that the EseN bacterial product is a virulence factor. Experiments here will identify how this EseN protein is involved in the disease development. These findings will increase basic knowledge about host-pathogen interactions. EseN has no equivalents in eukaryotes, and can therefore be an attractive target for indirect narrow-spectrum antibiotics. Findings from this project could be applied for disease prevention, disease control, and the development of a live-attenuated vaccine. Recently, Edwardsiellosis was also reported in other fish species that increases the importance of this work. The proposed work will also have a broad impact on research and research productivity at Southern University. It includes a mentoring program for undergraduate students and under-served high school students introduce them to research and to prepare them for careers in the Biological Sciences. The goal of this work is to determine the molecular mechanism(s) that the E. ictaluri T3SS effector EseN employs to accomplish its impact as a virulence factor on host physiology. This will be accomplished by investigating EseN modulation of host cell gene expression, determining EseN-host protein interactions, establishing phenotypic changes associated with specific gene mutations, and determining expression of genes involved in the host innate immune response. The E. ictaluri T3SS effector EseN is similar to Shigella OspF and Salmonella SpvC, which selectively dephosphorylate extracellular signal regulated kinase 1/2 (ERK1/2), p38, and c-Jun-N-terminal/stress-activated protein kinase (JNK) during infections, resulting in inactivation of mitogen-activated protein kinase (MAPK) signaling pathways. The EseN amino acid similarity to these other effectors, however, does not ensure similar activity, even if the biochemical activity of the homologous proteins is the same. Indeed, we find that EseN also targets the major vault protein and potentially phosphatidylinositide 3-kinase (PI3), in addition to ERK1/2. This demonstrates unique functions of EseN that are not described in its homologs. When these data are combined with the demonstrated high level of attenuation of an EseN knock-out mutant, we hypothesize that EseN is a major virulence factor that plays an essential role in manipulating host cytokine production and limiting induction of the host innate and adaptive immune responses. This project is jointly funded by Excellence in Research (EiR), and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.